Background DNA fragments that appeared to belong to an unidentifiedhuman herpesvirus were recently found in more than 90 percentof Kaposi's sarcoma lesions associated with the acquired immunodeficiencysyndrome (AIDS). These fragments were also found in 6 of 39tissue samples without Kaposi's sarcoma, including 3 malignantlymphomas, from patients with AIDS, but not in samples frompatients without AIDS.
Methods We examined the DNA of 193 lymphomas from 42 patientswith AIDS and 151 patients who did not have AIDS. We searchedthe DNA for sequences of Kaposi's sarcoma–associated herpesvirus(KSHV) by Southern blot hybridization, the polymerase chainreaction (PCR), or both. The PCR products in the positive sampleswere sequenced and compared with the KSHV sequences in Kaposi'ssarcoma tissues from patients with AIDS.
Results KSHV sequences were identified in eight lymphomas inpatients infected with the human immunodeficiency virus. Alleight, and only these eight, were body-cavity–based lymphomas— that is, they were characterized by pleural, pericardial,or peritoneal lymphomatous effusions. All eight lymphomas alsocontained the Epstein–Barr viral genome. KSHV sequenceswere not found in the other 185 lymphomas. KSHV sequences were40 to 80 times more abundant in the body-cavity–basedlymphomas than in the Kaposi's sarcoma lesions. A high degreeof conservation of KSHV sequences in Kaposi's sarcoma and inthe eight lymphomas suggests the presence of the same agentin both lesions.
Conclusions The recently discovered KSHV DNA sequences occurin an unusual subgroup of AIDS-related B-cell lymphomas, butnot in any other lymphoid neoplasm studied thus far. Our findingstrongly suggests that a novel herpesvirus has a pathogenicrole in AIDS-related body-cavity–based lymphomas.
In patients with the acquired immunodeficiency syndrome (AIDS)there is a probability of approximately 40 percent that cancerwill develop, especially Kaposi's sarcoma and non-Hodgkin'slymphoma.1,2,3,4 Chang et al.5 recently found evidence suggestingan infectious cause of Kaposi's sarcoma, an observation consistentwith those in previous epidemiologic studies.1,6,7,8,9,10,11Two novel DNA fragments were isolated from the Kaposi's sarcomalesions of patients with AIDS and identified in more than 90percent of such lesions, but they were not found in DNA samplesfrom patients without AIDS. These fragments were also identifiedin 6 of 39 tissues without Kaposi's sarcoma from patients withAIDS, including 3 malignant lymphomas. The base sequence ofthe DNA fragments and their flanking sequences had partial homologyto two herpesviruses, Epstein–Barr virus (EBV) and herpesvirussaimiri, both of which belong to the subfamily of Gammaherpesvirinae.5These data suggested the presence in AIDS-associated Kaposi'ssarcoma of a previously unidentified human herpesvirus, whichwe refer to as Kaposi's sarcoma–associated herpesvirus(KSHV).
Most AIDS-related non-Hodgkin's lymphomas are diffuse B-celllymphomas of the following types: small-noncleaved-cell (Burkitt'sand non-Burkitt's) lymphomas (40 percent), large-cell lymphomas(30 percent), and large-cell, immunoblastic plasmacytoid lymphomas(30 percent).12 Among the less common types found in patientsinfected with the human immunodeficiency virus (HIV)13 are thebody-cavity–based lymphomas. These may constitute a distinctsubgroup because of their unusual clinical, immunophenotypic,and molecular genetic characteristics.14,15,16,17 They growexclusively or mainly in the pleural, pericardial, and peritonealcavities as lymphomatous effusions, usually with no identifiabletumor mass throughout their clinical course. They have indeterminateimmunophenotypes but B-cell genotypes with clonal rearrangementsof the immunoglobulin genes. Furthermore, unlike many AIDS-relatedB-cell non-Hodgkin's lymphomas,18,19 the body-cavity–basedlymphomas that were previously analyzed frequently containedEBV and consistently had no rearrangements of the c-myc gene.14,20
An association between Kaposi's sarcoma and lymphoid cancerhas been noted in patients without AIDS,21,22 and a high riskof malignant lymphoma has been reported in patients with AIDS-relatedKaposi's sarcoma.23 However, the etiologic relation, if any,between these two neoplasms is unknown. Therefore, we investigateda clinicopathologically heterogeneous group of 193 AIDS-relatedand non–AIDS-related lymphoid neoplasms for KSHV sequences.The neoplasms studied included eight AIDS-related body-cavity–basedlymphomas.
Methods
Pathological Samples
A group of 183 well-characterized lymphoid neoplasms (32 ofwhich were from patients with AIDS and 151 of which were notAIDS-related) were selected from among neoplasms obtained inthe surgical-pathology laboratory of Columbia–PresbyterianMedical Center. Neoplasms were selected so that most categoriesof lymphoid neoplasia would be included (Table 1), but the selectionwas not intended to represent the actual frequency of each category.A preliminary analysis of 56 of these neoplasms (27 AIDS-relatedand 29 non–AIDS-related non-Hodgkin's lymphomas) had beenpreviously reported.5 That analysis found KSHV sequences inthree AIDS-related lymphomas, all of which were malignant lymphomatouseffusions. In the present study, to determine whether KSHV ispreferentially associated with AIDS-related body-cavity–basedlymphomas, we included 10 additional AIDS-related non-Hodgkin'slymphomas obtained at the Cedars–Sinai Medical Centerin Los Angeles, 5 of which were based in body cavities. Sixof the eight lymphomas of this type analyzed here and foundto be KSHV-positive have been described previously. Lymphoma1 corresponds to Patient 1 described by Chadburn et al.,20 lymphomas2 and 3 correspond to Patients 1 and 3 described by Knowleset al.,14 and lymphomas 4, 7, and 8 were reported by Walts etal.15 Lymphomas 1, 2, and 3 are the three AIDS-related lymphomasfound to be positive for KSHV by Chang et al.5
Table 1. Results of Screening for KSHV Sequences by Southern Blot Hybridization and PCR.
Heparin-treated peripheral blood, samples of effusion and bonemarrow aspirate, and tissue-biopsy specimens were collectedunder sterile conditions during standard diagnostic procedures.Mononuclear cells were isolated by Ficoll–Hypaque (PharmaciaFine Chemicals, Piscataway, N.J.) density-gradient centrifugation.Representative portions of each tissue specimen were routinelyfixed in buffered formalin, B5, or Bouin's solution and embeddedin paraffin, and sections stained with hematoxylin and eosinwere prepared. The remaining portions were embedded in a cryopreservativesolution (OCT, Tissue-Tek, Miles, Elkhart, Ind.) and storedat -70°C. The diagnosis of each specimen was based on acorrelative analysis of the clinical, morphologic, and immunophenotypiccharacteristics. The specimens were categorized according tothe Revised European–American Lymphoma Classificationsystem.24
Immunophenotypic Analysis
The immunophenotypic profiles of all neoplasms included in thisstudy were determined by flow cytometry (FACScan, Becton Dickinson,Mountain View, Calif.); immunoperoxidase staining of frozentissue sections, cytospin preparations, or paraffin-embeddedtissue sections, as previously described25; or a combinationof these methods. The number and type of antibodies used ineach case depended on the antibody panel needed to confirm thediagnosis and the amount of tissue available for study. Theantibody panels used to study lymphomas 1, 2, 3, 4, 7, and 8have been reported previously.14,15,20 The antibodies used tostudy lymphomas 5 and 6 included Dako-LC (leukocyte common antigen,or LCA [CD45]), Leu-14 (CD22), and L26 (CD20) (Dako, Santa Barbara,Calif.); Leu-1 (CD5) (Beckton Dickinson); and AE1/AE3 (cytokeratin)(Boehringer–Mannheim, Indianapolis). Antiserum to thekappa and lambda immunoglobulin light chains (Dako) was usedin the analysis.
DNA Extraction
Genomic DNA was extracted from cryopreserved mononuclear-cellsuspensions and tissue blocks by digestion with proteinase K,extraction with phenol–chloroform, and precipitation withethanol.26 An alternative salting-out procedure, not requiringorganic extraction, was used when a limited amount of tissuewas available.27
Southern Blot Hybridization
Five-microgram aliquots of genomic DNA were digested with theappropriate restriction endonucleases according to the manufacturer'sinstructions (Boehringer–Mannheim), subjected to electrophoresisin 0.8 percent agarose gels, denatured with alkali, neutralized,and transferred to nitrocellulose filters according to the methodof Southern.28 The filters were hybridized as previously described29to probes that had been labeled with phosphorus-32 by the random-primerextension method.30 Autoradiography was performed at -70°C,once for 16 hours and again for 14 days, to exclude the presenceof weak bands.
The presence of KSHV sequences was determined by hybridizingBamHI-digested DNA to 32P-labeled KS330Bam and KS631Bam probes.5To quantitate the sequences, the intensity of the hybridizationsignal in the DNA samples was compared directly with that ofDNA containing known molar amounts of these sequences. The latterwas prepared by combining 5 µg of KSHV-negative DNA (froma hyperplastic lymph node) with fivefold serial dilutions ofthe cloned KS631Bam fragment.
The c-myc oncogene was studied by hybridizing DNA digested byEcoRI and HindIII to a third exon probe (MC413RC).31 The presenceand clonality of EBV infection were determined by hybridizingBamHI-digested DNA to a terminal-repeat probe that detects EBVgenomic termini.32
Oligonucleotide Primers and Probes
All the oligonucleotides used for PCR amplification in thisstudy were synthesized by the solid-phase triester method. Thesequences of oligonucleotides used in the amplification andhybridization of KS330233 have been previously reported.5 Theprimers and probes for EBV included sets for the EBNA-2,EBNA-3C,and EBER regions and were derived from published sequences.33
Polymerase Chain Reaction and Hybridization
The conditions for the polymerase chain reaction (PCR) and hybridizationof KS330233Bam were as previously reported.5 The PCR and hybridizationsof EBV were performed as previously described.34
Sequencing of PCR Products
DNA sequencing of the PCR products of KS330233 was performedon the eight positive lymphomas. The PCR products were sequencedwith a Taq DyeDeoxy Terminator Cycle Sequencing method withan ABI 373A automated DNA sequencer (Applied Biosystems, FosterCity, Calif.). The two strands and two independent PCR productswere sequenced to exclude mismatches due to polymerase mistakes.
Statistical Analysis
Tests of significance were performed by a one-tailed Fisher'sexact test with Epi-Info 5.0 (USD, Stone Mountain, Ga.).
Results
Southern Blot Analysis of KSHV Sequences
For 191 of the 193 lymphoid neoplasms, DNA samples obtainedfor diagnostic purposes from 40 HIV-positive and 151 HIV-negativepatients were studied by Southern blot hybridization to detectKSHV sequences. Two neoplasms were not examined by Southernblot hybridization because of insufficient DNA. The pathologicaldiagnoses of the neoplasms are shown in Table 1. Six of the191 neoplasms tested with probes KS330Bam and KS631Bam werepositive for KSHV (Figure 1, Table 1). All six were body-cavity–basedlymphomas from patients with AIDS (chi-square = 160, by Fisher'sexact test; P<0.001), which we refer to henceforth as lymphomas1 through 6. DNA from the six lymphomas had much stronger hybridizationsignals than DNA from the Kaposi's sarcoma sample used as apositive control (Figure 1). The approximate copy number ofKSHV sequences in each lymphoma was obtained by comparing thehybridization signal for the lymphoma DNA to the signals forDNA containing known molar amounts of KSHV sequences (data notshown). We estimate that there was an average of 1 copy of theKSHV sequence per cell in the Kaposi's sarcoma tissue,5 as comparedwith 40 to 80 copies per cell in the malignant lymphomas.
Figure 1. Southern Blot Hybridization to Detect Kaposi's Sarcoma–AssociatedViral Sequences.
Lanes 5, 6, 8, 15, 16, and 17 show strong hybridization to probe KS631Bam and correspond to lymphomas 1 through 6, respectively. None of the other lymphomas shown in Table 1 hybridized with this probe. NC denotes negative control (HL-60 cell line), and KS Kaposi's sarcoma DNA (used as a positive control). The same results were obtained with the KS330Bam probe (data not shown).
PCR Analysis and Sequencing of KSHV in the Body-Cavity–Based Lymphomas
DNA from all 193 lymphoid neoplasms shown in Table 1 was analyzedafter PCR with primers KS330233F and KS330233R, which amplifya 233-base-pair (bp) fragment from the KS330Bam region. Twobody-cavity–based lymphomas (lymphoma 7 and lymphoma 8)were analyzed in addition to the 191 neoplasms studied by Southernblotting. All eight body-cavity–based lymphomas were positivefor KSHV, but none of the other 185 neoplasms showed an amplifiedproduct, even after hybridization with an internal oligonucleotideprobe (Table 1, Figure 2).
Figure 2. PCR Amplification of DNA from AIDS-Related Body-Cavity–Based Lymphomas, Using the KS330233 Primers.
The upper panel shows the ethidium bromide–stained agarose gel of the amplification products of DNA from a molecular-weight marker (M; HindIII-digested lambda and HaeIII-digested Phi-X DNA), water (H2O), and DNA from a negative control (NC; HL-60 cell line), a positive control (KS), and lymphomas 1 through 8. The lower panel shows specific hybridization of the PCR products to an internal oligonucleotide probe end-labeled with phosphorus-32, after transfer to nitrocellulose filters.
To determine similarities in the KSHV sequences from Kaposi'ssarcoma tissue and from the body-cavity–based lymphomas,we sequenced the 233-bp PCR band obtained for the eight lymphomas.A very high degree of conservation was found. The Kaposi's sarcomaand lymphoma DNA sequences differed only by one to four nucleotides,which resulted in substitutions of one or two amino acids. Bycontrast, a comparison of these sequences with the analogousregion of EBV35 revealed a difference of 114 bases. Thus, EBVhad 51 percent homology to KS330233 at the DNA level and 35percent homology at the protein level, whereas homology wasgreater than 98 percent in the amplified DNA sequences fromthe Kaposi's sarcoma tissue and the lymphomas. These findingsstrongly suggest that the sequences obtained by PCR from thebody-cavity–based lymphomas correspond to the same putativeagent previously identified in Kaposi's sarcoma and differ fromsequences in the analogous region of EBV.
Clinical, Morphologic, Immunophenotypic, and Molecular Characteristics of Body-Cavity–Based Lymphomas
Clinical Features
All eight patients with body-cavity–based lymphomas werehomosexual men ranging in age from 30 to 58 years (Table 2).In seven of the eight, the lymphoma presented as a malignanteffusion. In Patient 3, a lymphoma in the region of the rightsubmandibular gland was found five months before a lymphomatouspleural effusion appeared. The neoplastic cells in both lymphomaswere morphologically and immunophenotypically similar. We wereunable to assess the clonal relation of the two tumors or thepresence of KSHV sequences in the submandibular-gland lymphoma,because no tissue from the latter was available.
Table 2. Clinical Characteristics of Eight Homosexual Men with AIDS-Related Body-Cavity–Based Lymphomas.
Two patients had a history of Kaposi's sarcoma at the time ofthe lymphoma diagnosis; none had Kaposi's sarcoma subsequently.No Kaposi's sarcoma tissue was available from these patientswith which to assess the presence of KSHV sequences. The clinicaloutcome of all eight patients was poor, with a median survivalof three months after the drainage of the malignant effusions.
Cytomorphologic Features
The neoplastic cells were round or ovoid to polygonal and containedabundant cytoplasm, usually amphophilic to basophilic, and nucleithat ranged from large, round, and regular to highly irregularand pleomorphic, with one or more large prominent nucleoli.Many cells had plasmacytoid or immunoblastic features. Somebinucleated or multinucleated cells resembled Reed–Sternbergcells. Mitotic figures were numerous.
Immunophenotypes
All eight body-cavity–based lymphomas expressed CD45,as would be consistent with a hematolymphoid origin. Lymphoma6 expressed CD20 and CD22, but in all the other lymphomas therewas no expression of antigens restricted to the B-cell lineage,and no lymphoma expressed surface or cytoplasmic immunoglobulin.In addition, all eight lymphomas lacked antigens restrictedto the T-cell, myeloid, and monocyte lineages. However, therewas variable expression of activation-associated antigens HLA-DR,CD23, CD25, CD38, CDw70, and CD71,14,15,20 and three of fivelymphomas studied expressed epithelial membrane antigen, whichis often found in immunoblastic lymphomas and anaplastic large-celllymphomas.36,37,38 None expressed cytokeratin. Definitive assignmentto the B-cell lineage by immunophenotypic analysis was onlypossible, therefore, in one of the eight lymphomas.
Molecular Genetic Characteristics
All eight lymphomas contained clonal rearrangements of the immunoglobulingene, establishing their B-cell lineage (Table 3). Lymphomas1, 2, and 3 were previously shown not to have rearrangementsof the c-myc gene,14,20 and Southern blot hybridization of lymphomas4 and 5 showed germ-line configurations of c-myc (data not shown).Lymphomas 6, 7, and 8 were not analyzed because of insufficientDNA. Thus, the c-myc oncogene was not rearranged in any of thefive AIDS-related lymphomas analyzed.
Table 3. Molecular Analysis of Eight AIDS-Related Body-Cavity–Based Lymphomas Positive for KSHV and EBV Viral Sequences.
The presence and clonality of EBV were determined in six ofthe eight lymphomas by Southern blot hybridization with a terminal-repeatprobe.32 The detection of a single band in all six (Figure 3)indicates that EBV infection preceded the clonal expansion ofthe neoplastic cell population and was present in that population,instead of in normal cells present in the effusion. PCR analysisof the eight lymphomas was performed with primers derived fromthree regions of the EBV genome (EBNA-2, EBNA-3C, and EBER)to exclude the possibility of cross-hybridization with KSHVsequences and to permit the identification of EBV subtypes Aand B.33,34 All eight lymphomas were positive for EBV with thethree sets of primers, whereas the Kaposi's sarcoma samplesused as controls were negative (data not shown), thereby rulingout the possibility of cross-hybridization with KSHV sequences.EBV types A and B were both identified (Table 3), as was thecase in studies of other AIDS-related non-Hodgkin's lymphomas.39,40
Figure 3. Southern Blot Analysis for the Presence and Clonality of EBV Infection.
The hybridization signals for lymphomas 1 through 6 indicate the presence of EBV. NC denotes negative control (HL-60 cell line), and KS Kaposi's sarcoma DNA (an additional negative control). The detection of a single band with a probe from the terminal-repeat region of EBV demonstrates the presence of this virus in a clonal population.
Discussion
This report describes novel Kaposi's sarcoma–associated,herpesvirus-like DNA sequences in a distinct subgroup of AIDS-relatedmalignant lymphomas that are based in body cavities. We identifiedthese sequences in all 8 such lymphomas studied but not in anyof 34 other AIDS-related lymphoid neoplasms or in 151 lymphoidneoplasms that were not AIDS-related. The consistent presenceof KSHV sequences in this group of AIDS-related lymphoid cancersand their absence from other categories of lymphoid neoplasiasuggest a specific link between body-cavity–based lymphomasand the KSHV sequences. These body-cavity–based lymphomasprobably represent a distinct category of AIDS-related lymphomasbecause of their unusual clinical, morphologic, and immunophenotypiccharacteristics. The rearrangement of immunoglobulin genes,combined with the expression of cell-surface antigens associatedwith the late stages of B-cell differentiation, activation,or both in the absence of antigens associated with the earlyand middle stages of B-cell differentiation, suggests that body-cavity–basedlymphomas are the malignant counterpart of a mature stage ofB-cell development. These lymphomas are also consistent in containingEBV and in the absence of rearrangement of the c-myc gene. Allthese features, now complemented by the presence of KSHV sequences,support the view that these lymphomas are a distinct biologicentity.
The KSHV sequences analyzed thus far have been homologous withmembers of the Gammaherpesvirinae subfamily of herpesvirus,which characteristically replicates in lymphoblastoid cells.41KSHV is most homologous to EBV35 and herpesvirus saimiri,42with identical sequences for 30 to 50 percent of amino acids.Thus, KSHV is probably a novel member of the subfamily thatcontains these two viruses. It is well known that EBV immortalizesB cells in vitro and is associated with malignant lymphomas,including endemic Burkitt's lymphoma, AIDS-related non-Hodgkin'slymphomas, lymphoproliferative disorders occurring after transplantation,and Hodgkin's disease.43 Herpesvirus saimiri, a virus of squirrelmonkeys (Saimiri sciureus), can be isolated from the peripheral-bloodmononuclear cells of healthy animals, but it causes fulminantT-cell lymphomas in New World primates other than its naturalhosts.44 Herpesvirus saimiri can also transform human T lymphocytesso that they grow continuously in vitro.45 Thus, the two herpesviruseswith the most structural homology to KSHV sequences have theability to induce latent infection of peripheral-blood lymphocytesof their natural host, immortalize lymphocytes in vitro, andlead to the development of malignant lymphomas. We suggest thatKSHV may also be involved in lymphoid transformation.
In addition to KSHV sequences, all eight body-cavity–basedlymphomas studied here contained EBV sequences. Since EBV isnot found in Kaposi's sarcoma lesions that contain KSHV sequences,the presence of these two viruses in combination appears tobe unique to this type of lymphoma. It is well known that EBVcan immortalize B cells in vitro, but EBV alone may not be sufficientfor tumor development, as is exemplified by the complementationof the activated c-myc oncogene and EBV in Burkitt's lymphoma.46Thus, it is possible that KSHV acts in conjunction with EBVto induce full transformation. Genetic complementation can occurin vitro with dual viral infections. For example, Flamand etal.47 reported that infection by human herpesvirus-6 could activatethe EBV replicative cycle. Thus, although the specific interactionsbetween EBV and KSHV remain to be assessed, the two virusesmay interact with one another to induce neoplastic transformation,certain phenotypic features of body-cavity–based lymphomas,or both.
All the patients with AIDS in this study who had body-cavity–basedlymphomas were homosexual men. Since this group is at highestrisk for Kaposi's sarcoma, it may also be at highest risk forthese lymphomas. However, only two of the eight patients withbody-cavity–based lymphomas had Kaposi's sarcoma, an indicationthat KSHV-associated body-cavity–based lymphomas can occurindependently of Kaposi's sarcoma in patients with AIDS.
In conclusion, we have identified Kaposi's sarcoma–associated,herpesvirus-like DNA sequences in all eight body-cavity–basedlymphomas we examined. These eight lymphomas have features thatdistinguish them as a distinct clinicopathological entity. KSHVis also associated with Kaposi's sarcoma, but the neoplasticnature of Kaposi's sarcoma is controversial.22,48 In contrast,body-cavity–based lymphomas are clearly malignant. Theconsistent presence of KSHV sequences in these lymphomas suggeststhat a novel herpesvirus plays a part in their development.Our evidence suggests that KSHV may be a transforming virusin an unusual group of AIDS-related lymphomas.
Supported in part by a grant (EY06337) from the National Institutesof Health (to Dr. Knowles).
We are indebted to Drs. Milayna Subar, Becky Miller, and AaronBick for clinical information on the patients; to Drs. Yi FangLiu and Feng Bai for expert technical assistance; and to Dr.Riccardo Dalla-Favera for his helpful review and critique ofthe manuscript.
Source Information
From the Department of Pathology, The New York Hospital–Cornell Medical Center, New York (E.C., D.M.K.); the Department of Pathology (Y.C.) and the Division of Epidemiology (P.S.M.), School of Public Health, Columbia University, New York; and the Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, Cedars–Sinai Medical Center, Los Angeles (J.W.S.).
Address reprint requests to Dr. Cesarman at The New York Hospital–Cornell Medical Center, Department of Pathology, 525 E. 68th St., New York, NY 10021.
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